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Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial
Abstract
Background Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes.Methods In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Abeta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Abeta immunostaining (Abeta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model.Findings 20 participants--15 in the AN1792 group, five in the placebo group--died before follow-up started. A further 22 patients--19 in the AN1792 group, three in the placebo group--died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Abeta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in Abeta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group.Interpretation Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.
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“A study involving cognitively healthy adults showed that Aβ in CSF or the hippocampus increases after sleep deprivation or slow-wave sleep disruption, which indicates the complexity of Aβ kinetics [59, 60, 61].”
From Clinical trials of new drugs for Alzheimer disease (2020) · cites this paper as [61]
In the citing paper
“Several anti-Aβ therapeutic strategies are being pursued to treat AD; however, it is likely that treatment will need to begin during the preclinical phase to prevent or limit plaque accumulation to be beneficial in reducing the risk of developing AD (51, 52).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [51]
In the citing paper
“Recent clinical trials attempting to replicate the benefits of Aβ immunotherapy seen in mouse models have been primarily unsuccessful in preventing early cognitive decline in AD patients despite significantly decreasing the amyloid burden”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Holmes et al., 2008
In the citing paper
“While safety concerns caused this trial to terminate prematurely, subsequent clinical analyses were at best unimpressive [250, 251].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [251]
In the citing paper
“There have been cases in which individuals with mid- to late-stage clinical AD were administered anti-Aβ immunotherapy that partially cleared AβPs, but this clearance did not seem to mitigate NFT formation or the inexorable disease course (69-71).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [70]
In the citing paper
“Often neglected is the question of lesion turnover (i.e. AβPs being possibly reabsorbed during life so that they would not be “counted” at autopsy), which seems to occur in some subjects (70, 270).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [70]
In the citing paper
“Aβ vaccine trials also attest to the ability of the immune system to clear diffuse AβPs (69, 70, 271), but it is not known whether toxic APP metabolites or other plaque components remain after clearance of fibrillar Aβ-peptides (73, 272).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [70]
In the citing paper
“a subset of patients from the aborted Wyeth/ELAN active Aβ vaccine trial that were studied at autopsy showed Aβ plaque removal in the absence of cognitive improvement [75].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [75]
Citations
Cites
1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769
RetractedFolstein, M. F., Folstein, S. E., & McHugh, P. R. (1975) · Journal of Psychiatric Research · doi:10.1016/0022-3956(75)90026-6 · Cited by 88,282
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291
A new rating scale for Alzheimer's disease
(1984) · American Journal of Psychiatry · doi:10.1176/ajp.141.11.1356 · Cited by 4,175
Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse
Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., et al. (1999) · Nature · doi:10.1038/22124 · Cited by 3,160
HYMAN, B. T., & TROJANOWSKI, J. Q. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199710000-00002 · Cited by 1,542
Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease
Morgan, D., Diamond, D. M., Gottschall, P. E., Ugen, K. E., Dickey, C. A., Hardy, J., Duff, K., Jantzen, P. T., DiCarlo, G., Wilcock, D. M., et al. (2000) · Nature · doi:10.1038/35050116 · Cited by 1,506
Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report
Nicoll, J. A. R., Wilkinson, D., Holmes, C., Steart, P., Markham, H., & Weller, R. O. (2003) · Nature Medicine · doi:10.1038/nm840 · Cited by 1,397
Self-citationSubacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization
Orgogozo, J.-M., Gilman, S., Dartigues, J.-F., Laurent, B., Puel, M., Kirby, L. C., Jouanny, P., Dubois, B., Eisner, L., Flitman, S., et al. (2003) · Neurology · doi:10.1212/01.wnl.0000073623.84147.a8 · Cited by 1,356
Cited by
Sorted by citations
Items 701–800 of 1,000
Lee, M., Guo, J., Schwab, C., McGeer, E. G., & McGeer, P. L. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.12.005 · Cited by 27
“Later autopies on some cases showed that phagocytosis of deposits ad occurred but that areas with plaque removal lacked lusters of dystrophic neurites (Holmes et al., 2008; Nicoll t al., 2003).”
BackgroundAlzheimer’s Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective
Scarano, N., Musumeci, F., Casini, B., Brullo, C., D’Ursi, P., Fossa, P., Schenone, S., & Cichero, E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146980 · Cited by 32
“Immunotherapy approaches were also applied, including active immunization (through vaccines developed on the antigen peptide) and passive immunization (monoclonal antibodies directly targeting the undesired protein), not leading to encouraging results as cognitive improvement [197].”
Ito, M., Johansson, J., Strömberg, R., & Nilsson, L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017587 · Cited by 28
“A recent experimental study [6] reported that, although immunization with Ab resulted in clearance of the neuritic plaques in AD patients, this did not prevent progressive neurodegeneration.”
BackgroundNew and emerging treatments for Alzheimer's disease
Corbett, A., & Ballard, C. G. (2012) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.2012.675327 · Cited by 27
“However, there was no evidence of any clinical benefit and the trial was halted due to patients developing aseptic meningoencephalitis, thought to have been induced by cytotoxic T-cell activation [35].”
BackgroundCulibrk, R. A., & Hahn, M. S. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.583884 · Cited by 28
“, 2016), these results were rarely—if ever—recapitulated in clinical trials (Holmes et al., 2008; Salloway et al., 2011; Egan et al., 2018).”
BackgroundResultShimada, M., Abe, S., Takahashi, T., Shiozaki, K., Okuda, M., Mizukami, H., Klinman, D. M., Ozawa, K., & Okuda, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057606 · Cited by 27
“Aß peptide reduced the deposition of Aß in some individuals [10].”
BackgroundForlenza, O. V., Diniz, B. S., Teixeira, A. L., Stella, F., & Gattaz, W. F. (2013) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2012-3505 · Cited by 31
A short perspective on the long road to effective treatments for Alzheimer's disease
Reynolds, D. S. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14581 · Cited by 28
“However, there were conflicting results as to whether the patients experienced clinical benefit or not (Holmes et al., 2008; Vellas et al., 2009).”
ResultNeurobiology of cognitive disorders
Kurz, A., & Perneczky, R. (2009) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e328330588b · Cited by 27
Potential importance of B cells in aging and aging-associated neurodegenerative diseases
Biragyn, A., Aliseychik, M., & Rogaev, E. (2017) · Seminars in Immunopathology · doi:10.1007/s00281-016-0615-8 · Cited by 25
“Similarly, a passive administration of Aβ-specific Ab [42, 43] or an active immunization with Aβ(1–42) vac-”
BackgroundAn Expanded Role for Neuroimaging in the Evaluation of Memory Impairment
Desikan, R. S., Rafii, M. S., Brewer, J. B., & Hess, C. P. (2013) · American Journal of Neuroradiology · doi:10.3174/ajnr.a3644 · Cited by 27
Sakatani, K., Oyama, K., & Hu, L. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.588140 · Cited by 26
Pahnke, J., Bascuñana, P., Brackhan, M., Stefan, K., Namasivayam, V., Koldamova, R. P., Wu, J., Möhle, L., & Stefan, S. M. (2021) · Free Neuropathology · doi:10.17879/freeneuropathology-2021-3528 · Cited by 29
Medecigo, M., Manoutcharian, K., Vasilevko, V., Govezensky, T., Munguía, M. E., Becerril, B., Luz-Madrigal, A., Vaca, L. A., Cribbs, D. H., & Gevorkian, G. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.03.023 · Cited by 26
Logan, S. M., Sarkar, S. N., Zhang, Z., & Simpkins, J. W. (2011) · Brain Research · doi:10.1016/j.brainres.2011.01.038 · Cited by 27
Williams, J. H., Wilcock, G. K., Seeburger, J. L., Dallob, A. L., Laterza, O., Potter, W. Z., & Smith, A. D. (2011) · Alzheimer s Research & Therapy · doi:10.1186/alzrt64 · Cited by 26
Brain aging and late-onset Alzheimer's disease: many open questions
Behl, C. (2012) · International Psychogeriatrics · doi:10.1017/s104161021200052x · Cited by 25
“Trials of Aβ vaccination, which clears Aβ aggregates outside of cells, are ongoing, although current clinical data do not indicate that immunization improves cognition in humans (Holmes et al., 2008).”
BackgroundNew Genes and New Insights from Old Genes
Ringman, J. M., & Coppola, G. (2013) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/01.con.0000429179.21977.a1 · Cited by 27
Davis, P. R., Giannini, G., Rudolph, K., Calloway, N. T., Royer, C. M., Beckett, T. L., Murphy, M. P., Bresch, F., Pagani, D., Platt, T. L., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.09.007 · Cited by 26
A guide to using functional magnetic resonance imaging to study Alzheimer's disease in animal models
Asaad, M., & Lee, J. H. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.031724 · Cited by 26
“This disconnect could explain why some treatments that improve cognition in animals fail to do so in human patients (Doody et al., 2014; Holmes et al., 2008; Salloway et al., 2014; Vellas et al., 2013).”
Drabik, D., Chodaczek, G., & Kraszewski, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010018 · Cited by 26
“On the other hand, recent clinical trials showed that the elimination of Aβ does not affect the progression of AD [8].”
BackgroundSenescence in aging and disorders of the central nervous system
Swenson, B. L., Meyer, C. F., Bussian, T. J., & Baker, D. J. (2019) · Translational Medicine of Aging · doi:10.1016/j.tma.2019.01.002 · Cited by 24
Takamatsu, Y., Ho, G. J., Koike, W., Sugama, S., Takenouchi, T., Waragai, M., Wei, J., Sekiyama, K., & Hashimoto, M. (2017) · npj Parkinson s Disease · doi:10.1038/s41531-016-0001-1 · Cited by 26
“1b).(7,8) Adversely, serious complications, such as meningoencephalitis, were unexpectedly encountered leading to early trial discontinuation.”
BackgroundQiu, W. Q. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.05.024 · Cited by 25
“In addition, clinical trial drugs against a single component of AD pathology, Aβ, seem to only have modest effects on the disease (Holmes et al., 2008; Karran and De Strooper, 2016; Selkoe, 2013).”
Simpson, L. W., Szeto, G. L., Boukari, H., Good, T. A., & Leach, J. B. (2019) · Acta Biomaterialia · doi:10.1016/j.actbio.2020.05.030 · Cited by 24
Principles and requirements for stroke recovery science
Sommer, C., & Schäbitz, W. (2020) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20970048 · Cited by 25
“It is a little bit the same dilemma as in Alzheimer’s disease where the idea that removing beta-amyloid would enhance cognitive state failed since too much neurons had already been gone.(126) Another major problem in stroke recovery research is a substantial incongruity between preclinical and clinical studies concern…”
BackgroundTashima, T. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14020411 · Cited by 27
“Surprisingly, as a result, AD dementia some patients was found t progress, although their senile pl ques in the brain disappeared [16].”
BackgroundLucerón‐Lucas‐Torres, M., Cavero‐Redondo, I., Martínez‐Vizcaíno, V., Saz‐Lara, A., Pascual‐Morena, C., & Álvarez‐Bueno, C. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.863059 · Cited by 24
Deep brain stimulation: a novel strategy for treating Alzheimer's disease.
Lyketsos, C. G., Targum, S. D., Pendergrass, J. C., & Lozano, A. M. (2012) · Europe PMC (PubMed Central) · Cited by 25
Clinical Applications of a Peptide-Based Vaccine for Glioblastoma
Kanaly, C. W., Ding, D., Heimberger, A. B., & Sampson, J. H. (2009) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2009.09.001 · Cited by 24
“[118] It is important to note that the small study size would have made it extremely difficult to see a difference in clinical endpoints.”
BackgroundPreventing Alzheimer's disease by means of natural selection
Demetrius, L., & Driver, J. A. (2014) · Journal of The Royal Society Interface · doi:10.1098/rsif.2014.0919 · Cited by 24
“Tau immunotherapy: Hopes and hindrances”
Shahpasand, K., Shamloo, A. S., Nabavi, S. M., Lu, K. P., & Zhou, X. Z. (2017) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2017.1393594 · Cited by 25
“there was a need to identify and study alternative prophylactic therapies.(1,2) Later research findings following Phase III Ab antibody trials supported this finding,(2) and a more recent Phase II trial of an Ab antibody was reported to exhibit a broad reactivity with various forms of Ab.”
BackgroundSilva, K. D., Brown, M. E., & McLaurin, J. (2009) · Vaccine · doi:10.1016/j.vaccine.2008.12.044 · Cited by 25
Kawaguchi, K., Kitaguchi, N., Nakai, S., Murakami, K., Asakura, K., Mutoh, T., Fujita, Y., & Sugiyama, S. (2010) · Journal of Artificial Organs · doi:10.1007/s10047-010-0482-3 · Cited by 24
Tau Phosphorylation and Aggregation as a Therapeutic Target in Tauopathies
Badiola, N., Suárez‐Calvet, M., & Lleó, A. (2010) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152710793237403 · Cited by 26
“However, as results obtained so far with anti-amyloid therapies in AD are modest [2], interest in disease-modifying therapies based on tau has grown.”
BackgroundToly‐Ndour, C., Lui, G., Nunes, M. M., Bruley-Rosset, M., Aucouturier, P., & Dorothée, G. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003953 · Cited by 27
“A follow-up study on a group of AN1792 patients suggested that the level of vaccine-induced Abs correlated with the clearance of amyloid plaques but not with clinical response (27).”
BackgroundSemagacestat's fall: where next for AD therapies?
(2013) · Nature Medicine · doi:10.1038/nm.3365 · Cited by 24
Smith, G. S., Protas, H., Kuwabara, H., Savonenko, A., Nassery, N., Gould, N. F., Kraut, M., Avramopoulos, D., Holt, D., Dannals, R. F., et al. (2023) · NeuroImage: Clinical · doi:10.1016/j.nicl.2023.103322 · Cited by 22
Alzheimer’s Disease Immunotherapy: Current Strategies and Future Prospects
Aljassabi, A., Zieneldien, T., Kim, J., Regmi, D., & Cao, C. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231163 · Cited by 28
“OtherversionsincludeshorterA (cid:2) 1 – 42 segments where a Th-cell epitope has been introduced, and the last version comprises a short A (cid:2) 1 – 42 peptide coupled with a protein carrier or virus-like particles, all with the intention of producing endogenous antibodies against A (cid:2) [50].”
Biomarkers for glioma immunotherapy: the next generation
Sims, J. S., Ung, T. H., Neira, J. A., Canoll, P., & Bruce, J. N. (2015) · Journal of Neuro-Oncology · doi:10.1007/s11060-015-1746-9 · Cited by 25
Chen, Y., Wei, G., Zhao, J., Nussinov, R., & Ma, B. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00364 · Cited by 23
Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes
Valenza, M., Facchinetti, R., Menegoni, G., Steardo, L., & Scuderi, C. (2021) · Biomolecules · doi:10.3390/biom11040600 · Cited by 25
“Additionally, the reduction of Aβ load by immunotherapy does not improve cognition in AD patients [72].”
BackgroundMolecular drug targets and therapies for Alzheimer’s disease
Singh, D. B., Gupta, M., Kesharwani, R. K., Sagar, M., Dwivedi, S., & Misra, K. (2014) · Translational Neuroscience · doi:10.2478/s13380-014-0222-x · Cited by 25
Olkhanud, P. B., Mughal, M., Ayukawa, K., Malchinkhuu, E., Bodogai, M., Feldman, N. H., Rothman, S. M., Lee, J.-H., Chigurupati, S., Okun, E., et al. (2012) · Vaccine · doi:10.1016/j.vaccine.2011.12.136 · Cited by 25
“Preclinical studies demonstrated that Aβ deposits can be reduced by passive administration of Aβ-specific antibody [6-8] or by active immunization with Aβ(1-42) [9-11].”
BackgroundGhosal, K., & Pimplikar, S. W. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.04.020 · Cited by 24
Active vaccination with ankyrin G reduces β-amyloid pathology in APP transgenic mice
Chadha, A. S., Merlini, M., Shetty, A., Tackenberg, C., Bali, J., Ferretti, M. T., McAfoose, J., Kulic, L., Bernreuther, C., Welt, T., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.70 · Cited by 25
Hopeahainol A attenuates memory deficits by targeting β‐amyloid in APP / PS 1 transgenic mice
Zhu, X., Ye, L., Ge, H. M., Chen, L., Jiang, N., Qian, L., Li, L., Liu, R., Shen, J., Zhang, S., et al. (2012) · Aging Cell · doi:10.1111/acel.12022 · Cited by 23
“Clinical trials showed that immunization with Ab42 could clear the amyloid plaques in patients with AD, but it did not prevent progressive neurodegeneration (Holmes et al., 2008).”
BackgroundMedical bioremediation of age-related diseases
Mathieu, J. M., Schloendorn, J., Rittmann, B. E., & Alvarez, P. J. J. (2009) · Microbial Cell Factories · doi:10.1186/1475-2859-8-21 · Cited by 26
Aβ-Degrading Proteases: Therapeutic Potential in Alzheimer Disease
Leissring, M. A. (2016) · CNS Drugs · doi:10.1007/s40263-016-0364-1 · Cited by 26
“Active immunization proved highly effective in removing brain Ab in mouse models [36–40] as well as in humans [41], and early studies showed some evidence of blunting cognitive decline in some patients with AD [42].”
BackgroundPathogenesis of Alzheimer’s Disease
Castellani, R. J., Plascencia‐Villa, G., & Perry, G. L. (2022) · Springer eBooks · doi:10.1007/978-3-031-15080-7_162 · Cited by 24
Antibody Therapy in Neurodegenerative Disease
Southwell, A. L., & Patterson, P. H. (2010) · Reviews in the Neurosciences · doi:10.1515/revneuro.2010.21.4.273 · Cited by 25
Mapping Out Biomarkers for Alzheimer Disease
Breteler, M. M. B. (2011) · JAMA · doi:10.1001/jama.2010.2017 · Cited by 24
“This may also explain why immunization against -amyloid 42 can lead to amyloid plaque clearance but not diminish further neurodegeneration and the clinical symptoms of dementia.(8) Studies with Pittsburgh compound B imaging have suggested that amyloid imaging may be a marker for developing AD pathology rather than for…”
Modrego, P. J., & Lobo, A. (2019) · Neurodegenerative Disease Management · doi:10.2217/nmt-2019-0006 · Cited by 24
The FDA Approves Aducanumab for Alzheimer’s Disease, Raising Important Scientific Questions1
de la Torre, J. C., & Gonzalez-Lima, F. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210736 · Cited by 24
Antibody Engineering for Optimized Immunotherapy in Alzheimer's Disease
Sumner, I. L., Edwards, R. A., Asuni, A. A., & Teeling, J. L. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00254 · Cited by 24
“While these studies showed that systemic administration of Aβ1-42-targeting antibodies clear amyloid plaques, they do not prevent progressive cognitive decline in these patients (Holmes et al., 2008).”
BackgroundMulti-mechanical waves against Alzheimer’s disease pathology: a systematic review
Monteiro, F., Sotiropoulos, I., Carvalho, Ó. S. N., Sousa, N., & Silva, F. S. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00256-z · Cited by 23
“For this reason, many researchers have focused on immunotherapies to increased Aβ clearance through administration of immunotherapeutic agents, both related and non-related with microglial activation [94], although non-satisfactory results have been obtained in clinical trials [95].”
Active DNA Aβ42 vaccination as immunotherapy for Alzheimer disease
Lambracht‐Washington, D., & Rosenberg, R. N. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0037-6 · Cited by 23
Transcriptional downregulation of FAM3C/ILEI in the Alzheimer’s brain
Watanabe, N., Nakano, M., Mitsuishi, Y., Hara, N., Mano, T., Iwata, A., Murayama, S., Suzuki, T., Ikeuchi, T., & Nishimura, M. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab226 · Cited by 23
Monoclonal Antibody Therapy For Malignant Glioma
Chen, K. S., & Mitchell, D. A. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3146-6_10 · Cited by 25
Counts, S., Ray, B., Mufson, E. J., Perez, S. E., He, B., & Lahiri, D. K. (2014) · Journal of Clinical Immunology · doi:10.1007/s10875-014-0020-9 · Cited by 24
Hallé, M., Tribout-Jover, P., Lanteigne, A.-M., Boulais, J., St-Jean, J. R., Jodoin, R., Girouard, M., Constantin, F., Migneault, A., Renaud, F., et al. (2015) · Journal of Immunological Methods · doi:10.1016/j.jim.2015.05.002 · Cited by 24
Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease
Clark, I. A., & Vissel, B. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.07.030 · Cited by 23
Immunogenic properties of amyloid beta oligomers
Dalgediene, I., Lasickiene, R., Budvytyte, R., Valincius, G., Morkuniene, R., Borutaite, V., & Zvirbliene, A. (2013) · Journal of Biomedical Science · doi:10.1186/1423-0127-20-10 · Cited by 22
Youn, H., & Jeong, H. (2018) · Journal of Korean Medical Association · doi:10.5124/jkma.2018.61.12.758 · Cited by 23
Liu, N., Haziyihan, A., Zhao, W. G., Chen, Y., & Chao, H. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00434-9 · Cited by 21
“For example, the Aβ vaccines UB-311 and ACC-001 have been discontinued because they led to meningoencephalitis in AD patients [85, 86].”
BackgroundGene Therapy for Parkinsons and Alzheimers Diseases: from the Bench to Clinical Trials
Nobre, R. J., & de Almeida, L. P. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211798072472 · Cited by 22
“Importantly, a significant number of patients that did not develop encephalitis still developed Alzheimer disease showing that there are still some uncertainties regarding this approach, particularly regarding the specificity of the immune-mediated removal of the A peptide [144].”
BackgroundEffect of rice-expressed amyloid β in the Tg2576 Alzheimer's disease transgenic mouse model
Nojima, J., Maeda, A., Aoki, S., Suo, S., Yanagihara, D., Watanabe, Y., Yoshida, T., & Ishiura, S. (2011) · Vaccine · doi:10.1016/j.vaccine.2011.06.073 · Cited by 22
Diverse Molecular Targets for Therapeutic Strategies in Alzheimer's Disease
Han, S.-H., & Mook‐Jung, I. (2014) · Journal of Korean Medical Science · doi:10.3346/jkms.2014.29.7.893 · Cited by 23
“Also, clinical evaluation in human AD patients failed to replicate the identical results as in the animal AD model, showing unsynchronized phenomena between reduced Aβ plaque and rescue of neurodegeneration during AD progression (75).”
ResultHara, H., Ono, F., Nakamura, S., Matsumoto, S., Jin, H., Hattori, N., & Tabira, T. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160514 · Cited by 22
Murakami, K., Masuda, Y., Shirasawa, T., Shimizu, T., & Irie, K. (2010) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/j.1447-0594.2010.00598.x · Cited by 22
Wang, S., Liu, J., Ji, W., Wen-Jiao, C. H. E. N., Fu, Q., Feng, L., & Ma, S. (2014) · Chinese Journal of Natural Medicines · doi:10.1016/s1875-5364(14)60135-7 · Cited by 22
“Since several trials against anti-Aβ antibody have failed ([6-10]), the key role of Aβ in AD is questioned, while AGEs and their role in AD receive more attention.”
BackgroundMollica, A., Stefanucci, A., Costante, R., & Pinnen, F. (2012) · Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry · doi:10.2174/187152312803476246 · Cited by 21
Fessel, J. (2017) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.4730 · Cited by 24
Shimada, H., Ataka, S., Takeuchi, J., Mori, H., Wada, Y., Watanabe, Y., & Miki, T. (2011) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988711409410 · Cited by 21
“Pittsburgh compound B-negative dementia should be accounted for when developing an anti-amyloid treatment of AD.15 Further clinical studies are required to completely understand the pathological characteristics of such PiB-negative patients with dementia.”
BackgroundInfluentialScreening Techniques for Drug Discovery in Alzheimer’s Disease
Maniam, S., & Maniam, S. (2024) · ACS Omega · doi:10.1021/acsomega.3c07046 · Cited by 21
Mitochondrial therapeutics in Alzheimer's disease and Parkinson's disease
Hoekstra, J. G., Montine, K. S., Zhang, J., & Montine, T. J. (2011) · Alzheimer s Research & Therapy · doi:10.1186/alzrt83 · Cited by 21
Roher, A. E., Maarouf, C. L., & Kokjohn, T. A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150757 · Cited by 22
“In the AN-1792 clinical trials, neuropathology and neurochemical analyses hinted that the anti-A antibodies reached their targets [81–87].”
BackgroundLi, Y., Liu, Y., Wang, Z., & Jiang, Y. (2013) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2013.838555 · Cited by 21
“However, survival rate or the time-to-severe dementia was not improved by AN1792-treated patients [17].”
BackgroundFessel, W. J. (2017) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317517698790 · Cited by 21
Membrane Aging as the Real Culprit of Alzheimer’s Disease: Modification of a Hypothesis
Yu, Q., & Zhong, C. (2017) · Neuroscience Bulletin · doi:10.1007/s12264-017-0192-4 · Cited by 21
Lee, D., Lee, G., & Yoon, D. S. (2018) · The Analyst · doi:10.1039/c7an02013a · Cited by 20
Widodo, S. S., Hutchinson, R. A., Fang, Y., Mangiola, S., Neeson, P. J., Darcy, P. K., Barrow, A. D., Hovens, C. M., Dinevska, M., Stylli, S. S., et al. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02801-7 · Cited by 20
Misframed Proteins and Neurodegeneration: A Novel View on Alzheimer’s and Parkinson’s Diseases
Dennissen, F. J. A., Kholod, N., Steinbusch, H. W. M., & van Leeuwen, F. W. (2010) · Neurodegenerative Diseases · doi:10.1159/000285510 · Cited by 21
“For the majority of Alzheimer’s disease (AD) and Parkinson’s disease (PD) cases (i.e. the sporadic forms), no suitable explanations are available. For AD, the amyloid cascade hypothesis has received the most attention, but it appears that other hypotheses are necessary to explain a multifactorial disease such as AD; e…”
BackgroundA Comparative Evaluation of a Novel Vaccine in APP/PS1 Mouse Models of Alzheimer’s Disease
Carrera, I., Etcheverrı́a, I., Fernández‐Novoa, L., Lombardi, V., Lakshmana, M. K., Cacabelos, R., & Vigo, C. (2015) · BioMed Research International · doi:10.1155/2015/807146 · Cited by 20
Nizzari, M., Barbieri, F., Gentile, M. T., Passarella, D., Caorsi, C., Diaspro, A., Taglialatela, M., Pagano, A., Colucci-D'Amato, L., Florio, T., et al. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-101590 · Cited by 21
Harnessing the Immune System for Treatment and Detection of Tau Pathology
Congdon, E. E., Krishnaswamy, S., & Sigurdsson, E. M. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132435 · Cited by 20
“some plaque associated tau lesions [10, 12–17].”
Immunotherapy for Alzheimer’s Disease
Farlow, M. R., & Brosch, J. R. (2013) · Neurologic Clinics · doi:10.1016/j.ncl.2013.03.012 · Cited by 20
Scherlek, A. A., Kozberg, M. G., Nicoll, J. A. R., Perosa, V., Freeze, W. M., van der Weerd, L., Bacskai, B. J., Greenberg, S. M., Frosch, M. P., Boche, D., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac021 · Cited by 20
“32 Our histopathological fi ndings are in line with previous observations in CAA autopsy cases with documented cortical super fi cial siderosis during life and are indicative of bleeding from the leptomeningeal blood vessels in the context of severe CAA.”
InfluentialSelf-citationAmyloid-β: A potential mediator of aging-related vascular pathologies
Khan, F., & Qiu, H. (2023) · Vascular Pharmacology · doi:10.1016/j.vph.2023.107213 · Cited by 22
Immunotherapy: An emerging treatment option for neurodegenerative diseases
Mukherjee, A., Biswas, S., & Roy, I. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.103974 · Cited by 22
Kelley, C. M., Perez, S. E., Overk, C., Wynick, D., & Mufson, E. J. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-102097 · Cited by 20
Vasilevko, V., Pop, V., Kim, H. J., Saing, T., Glabe, C. C., Milton, S. C. F., Barrett, E. G., Cotman, C. W., Cribbs, D. H., & Head, E. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.04.014 · Cited by 19
“These patients showed significantly less Aβ plaque deposition, however, none of the immunized patients showed any slowing of dementia and all eventually progressed to end stage disease (Holmes et al., 2008).”
BackgroundYang, D., Shi, S., Zheng, L., Yao, T., & Ji, L. (2010) · Biopolymers · doi:10.1002/bip.21527 · Cited by 20
Tachi, N., Hashimoto, Y., & Matsuoka, M. (2012) · Biochemical Journal · doi:10.1042/bj20100993 · Cited by 20
Turano, E., Busetto, G., Marconi, S., Guzzo, F., Farinazzo, A., Commisso, M., Bistaffa, E., Angiari, S., Musumeci, S., Sotgiu, S., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.12.033 · Cited by 20
“…in this regard were the results from recent clinical trials aiming to decrease Aβ burden in sporadic AD, where the reduction of cerebral amyloid plaques was not accompanied by substantial clinical benefits (Holmes et al., 2008; Lemere and Masliah, 2010; Doody et al., 2014; Salloway et al., 2014).”
Wang, F., Liu, H., Shen, X., Ao, H., Moore, N., Gao, L., Chen, L., Hu, H., Ma, H., Yang, Z., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.029 · Cited by 20
Cao, Y., Wang, J.-C., Zhu, K., Zhang, H., Wang, G., & Liu, H. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.266061 · Cited by 20
“Although the clinical trial for AN1792 vaccine failed, long-term follow-up of subjects has demonstrated that active immunization with AN1792 vaccine reduced Aβ load (Nicoll et al., 2003) and attenuated neurological deficits (Bayer et al., 2005; Holmes et al., 2008; Vellas et al., 2009).”
Lambracht‐Washington, D., Fu, M., Frost, P., & Rosenberg, R. N. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-017-0257-7 · Cited by 20
“In regard to the antibody titers found in this study, it is important to note that antibody titers of 1:2000 found in patients in the AN1792 clinical trial had been shown to be sufficient for removal of Aβ from the brain and significant reduction of the plaque load [8].”
Clinical implications of extracellular vesicles in neurodegenerative diseases
Vinaiphat, A., & Sze, S. K. (2019) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2019.1657407 · Cited by 20
Monteiro‐Fernandes, D., Silva, J. M., Soares‐Cunha, C., Dalla, C., Kokras, N., Arnaud, F., Billiras, R., Zhuravleva, V., Waites, C. L., Bretin, S., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0794-5 · Cited by 20
Metadata
- Authors
- Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R. W., Bullock, R., Love, S., Neal, J. W., Zotova, E., & Nicoll, J. A.
- Affiliations
- Moorgreen Hospital (GB)
- University of Southampton (GB)
- Isfahan University of Medical Sciences (IR)
- Royal United Hospital (GB)
- University of Bristol (GB)
- University of Wales (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 372
- Issue
- 9634
- Pages
- 216-223
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2152446053
- Semantic Scholar
- 08e069e9f584a9125571b66eb799997753fe6d98
- Cited by
- 1,416
- References
- 33
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 30 · 2023: 34 · 2022: 46 · 2021: 52 · 2020: 58 · 2019: 61 · 2018: 58 · 2017: 73 · 2016: 71 · 2015: 82 · 2014: 113 · 2013: 115 · 2012: 120
- FWCI
- 102.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- University of Oxford
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid plaques, dental plaque removal, amyloid load, long-term clinical outcomes, survival, dementia progression, postmortem neuropathology, immunotherapy safety and efficacy, autopsy
- MeSH terms
- Aged, Alzheimer Disease, Antibody Formation, Follow-Up Studies, Humans, Randomized Controlled Trials as Topic, Amyloid beta-Peptides, Clinical Trials, Phase I as Topic, Plaque, Amyloid
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